【摘要】：研究背景 高強(qiáng)度聚焦超聲(High Intensity Focused Ultrasound, HIFU)作為一種新興的非侵入性治療手段,已經(jīng)應(yīng)用于臨床多種疾病的治療,諸如子宮肌瘤、肝癌、腎癌、骨腫瘤、乳腺癌等實(shí)體腫瘤和過(guò)敏性鼻炎、關(guān)節(jié)炎、宮頸炎等非腫瘤性疾病中,并取得了良好的治療效果。HIFU治療的原理是將體外低能量的超聲束聚焦到體內(nèi)病灶處并形成高能量的焦點(diǎn),利用超聲對(duì)生物組織的熱效應(yīng)、空化效應(yīng)和機(jī)械效應(yīng)等使焦點(diǎn)處的溫度瞬間升至56℃以上,導(dǎo)致該處組織形成不可逆的凝固性壞死,但不影響周?chē)恼＝M織,從而達(dá)到治療的目的。 作為非侵入性治療方式,必須要有可靠而準(zhǔn)確的監(jiān)控方式。目前所用的監(jiān)控方式有B超和磁共振(Magnetic Resonance Imaging, MRI)。其中,B超監(jiān)控具有實(shí)時(shí)性好、價(jià)格低廉、與HIFU設(shè)備兼容性好等優(yōu)點(diǎn),且B超監(jiān)控的HIFU設(shè)備己大量應(yīng)用于臨床中。B超監(jiān)控的原理是以HIFU輻照后即刻B超聲像圖中強(qiáng)回聲的出現(xiàn)作為一個(gè)單元治療完成的標(biāo)志。但是,對(duì)于該強(qiáng)回聲出現(xiàn)的原因,目前尚不甚明了有部分學(xué)者指出,出現(xiàn)強(qiáng)回聲主要是HIFU致靶區(qū)空化行為產(chǎn)生的空化泡所致；也有學(xué)者指出是靶區(qū)溫度上升產(chǎn)生的沸騰泡所致。 HIFU輻照后組織中所形成的凝固性壞死應(yīng)為橢球形,但在某些情況下,壞死形態(tài)會(huì)發(fā)生變化,呈水滴狀甚至三角形。關(guān)于該形態(tài)變化的原因,爭(zhēng)論也集中在輻照中對(duì)HIFU束遮擋的空化泡和沸騰泡之間。 目前HIFU治療所用的主要機(jī)制是熱機(jī)制,但是其另一機(jī)制——空化機(jī)制發(fā)生時(shí),可以在局部產(chǎn)生高溫、高壓、高速射流等極端物理現(xiàn)象,從而對(duì)組織造成損傷。且有研究者指出,HIFU輻照中強(qiáng)回聲的出現(xiàn)意味著過(guò)度治療,即能量的過(guò)度沉積而致靶區(qū)的溫度過(guò)高,會(huì)影響到治療的安全性。另有研究者指出,脈沖HIFU (pulsed High Intensity Focused Ultrasound, pHIFU)的應(yīng)用可以避免靶區(qū)的明顯溫升,從而利用其非熱效應(yīng)。 基于上述背景,本研究基于一臺(tái)商業(yè)HIFU腫瘤治療系統(tǒng),選擇不同的輻照參數(shù),輻照離體牛肝組織,以在焦域處產(chǎn)生空化泡和/或沸騰泡,在輻照后即刻采集B超聲像圖,與輻照前同一位置的聲像圖進(jìn)行比較,并解剖牛肝組織,初步研究HIFU輻照中空化泡和沸騰泡對(duì)焦域處回聲增強(qiáng)和凝固性壞死形態(tài)改變的影響。此外,本研究還利用pHIFU輻照離體牛肝組織,利用其非熱效應(yīng),特別是空化效應(yīng)對(duì)組織造成損傷,并對(duì)其損傷機(jī)制和B超監(jiān)控進(jìn)行了初步研究。 目的 1.初步研究HIFU輻照后即刻B超聲像圖中強(qiáng)回聲出現(xiàn)的原因； 2.初步研究HIFU輻照所致凝固性壞死形態(tài)發(fā)生改變的原因； 3.利用pHIFU輻照離體組織,研究其造成非熱損傷的可行性; 4.初步研究pHIFU輻照所致非熱損傷的機(jī)制及B超監(jiān)控的可行性。 方法 1.HIFU輻照離體組織中的空化和沸騰對(duì)B超強(qiáng)回聲及凝固性壞死形態(tài)的影響 1.1實(shí)驗(yàn)材料：屠宰后6小時(shí)內(nèi)的新鮮離體牛肝組織,取血管和結(jié)締組織較少處切成約100mm×100mm×60mm大小的方塊,置于生理鹽水中脫氣30min待用； 1.2實(shí)驗(yàn)儀器與設(shè)備：JC200型HIFU腫瘤治療系統(tǒng)(凹球面聚焦,B超監(jiān)控,頻率0.94MHz)；被動(dòng)空化檢測(cè)(Passive Cavitation Detection, PCD)系統(tǒng)：平面壓電換能器(中心頻率0.5MHz和5MHz),LabVIEW開(kāi)發(fā)平臺(tái),水浸數(shù)據(jù)線(xiàn)等；溫度采集系統(tǒng)：E型熱電偶,溫度巡檢儀,數(shù)據(jù)采集程序和計(jì)算機(jī)等。 1.3實(shí)驗(yàn)方法： (1)校正HIFU聲輸出； (2)使用HIFU定點(diǎn)輻照脫氣后的離體牛肝組織,深度為20mm,輻照參數(shù)為：50W×10s、50W×80s、100W×10s、150W×5s、200W×2s和200W×5s； (3)HIFU輻照過(guò)程中使用PCD系統(tǒng)采集焦域處的聲發(fā)射信號(hào)(acoustic emissions,主要為空化信號(hào))后對(duì)該信號(hào)進(jìn)行快速傅立葉變換(Fast Fourier Trans form at ion, FFT)后記錄次諧波和四次諧波的幅值隨輻照時(shí)間的變化情況。另對(duì)該信號(hào)進(jìn)行帶通濾波(3～7MHz)和帶阻濾波(濾除通帶內(nèi)的高次諧波)后計(jì)算其均方根(Root Mean Square,RMS),并得到RMS隨輻照時(shí)間的變化曲線(xiàn)； (4)HIFU輻照中使用溫度采集系統(tǒng)記錄焦域處的溫度,并繪制其隨輻照時(shí)間變化的曲線(xiàn)；重復(fù)6次實(shí)驗(yàn),對(duì)焦域處的最高溫度進(jìn)行統(tǒng)計(jì)學(xué)分析； (5)HIFU輻照后即刻采集B超聲像圖,并與輻照前同一位置的B超聲像圖進(jìn)行比較,重復(fù)20次實(shí)驗(yàn),對(duì)結(jié)果進(jìn)行分析； (6)HIFU輻照結(jié)束后,將牛肝組織切成1～2mm厚的薄片,找到凝固性壞死最大面積所在層面,觀(guān)察壞死的形態(tài)。2.脈沖HIFU輻照離體組織所致非熱損傷的初步實(shí)驗(yàn)研究 2.1實(shí)驗(yàn)材料：同上； 2.2實(shí)驗(yàn)儀器與設(shè)備：同上； 2.3實(shí)驗(yàn)方法： (1)校正HIFU聲輸出,并調(diào)整HIFU輸出為脈沖模式； (2)使用pHIFU定點(diǎn)輻照脫氣后的離體牛肝組織,輻照參數(shù)見(jiàn)后表； (3)輻照中使用PCD系統(tǒng)采集焦域處的空化信號(hào),并進(jìn)行FFT變換,焦域處的溫度由溫度采集系統(tǒng)獲取后繪制其隨輻照時(shí)間的變化曲線(xiàn),并得到6次輻照中焦域處的最高溫度； (4)輻照后即刻,采集B超聲像圖,并與輻照前同一位置的B超聲像圖進(jìn)行比較,計(jì)算靶區(qū)灰度的變化值； (5)輻照結(jié)束后,將牛肝組織切成厚為1～2mm的薄片,找到損傷最大面積所在層面,觀(guān)察損傷形態(tài),選取標(biāo)本進(jìn)行hematoxylin-eosin (HE)染色,并在光鏡下觀(guān)察。 聲功率(W)占空比脈沖重復(fù)頻率(Hz)輻照時(shí)間(s)深度(mm)1%602%305004203%204%15結(jié)果 1.所有參數(shù)的HIFU輻照中均可見(jiàn)次諧波出現(xiàn)；聲功率為50W和100W的HIFU輻照中寬帶噪聲的RMS未見(jiàn)增大；聲功率為150W的HIFU輻照中RMS開(kāi)始較小,后增大；聲功率為200W的HIFU輻照開(kāi)始RMS即較大,在5s的輻照中有減弱趨勢(shì)； 2.參數(shù)為50W×10s、50W×80s、100W×10s、150W×5s、200W×2s、200W×5s和的HIFU輻照中焦域處的最高溫度分別為62.40±6.50℃、93.61±2.46℃、67.29±2.56℃、77.84±6.96℃、75.69±5.18℃和88.10±4.06℃； 3.參數(shù)為50W×10s、100W×10s、150W×5s和200W×2s的HIFU輻照后即刻B超聲像圖中未見(jiàn)強(qiáng)回聲(強(qiáng)回聲出現(xiàn)率分別為0、15%、10%和5%),凝固性壞死形態(tài)較規(guī)則；另2個(gè)參數(shù)的HIFU輻照后即刻B超聲像圖中觀(guān)察到強(qiáng)回聲出現(xiàn)(強(qiáng)回聲出現(xiàn)率均為95%),輻照后壞死形態(tài)發(fā)生改變； 4.參數(shù)為50W×80s和200W×5s的HIFU輻照中四次諧波可見(jiàn)增加,且200W聲功率的HIFU輻照中四次諧波增加后寬帶噪聲的RMS減�。�5. pHIFU輻照后所致非熱損傷為洞狀,無(wú)固態(tài)內(nèi)容物； 6.500W聲功率下,1%～4%占空比的pHIFU輻照中焦域處的最高溫度分別為41.19±1.42℃,45.73±1.92℃,53.07±2.09℃和64.13±2.56℃,且輻照中均可見(jiàn)明顯的寬帶噪聲； 7. pHIFU輻照后即刻B超聲像圖中靶區(qū)灰度減小,回聲變?nèi)酢?結(jié)論 1. HIFU輻照中焦域處的空化泡和沸騰泡對(duì)輻照結(jié)果的影響不同； 2. HIFU輻照后即刻B超聲像圖中強(qiáng)回聲的出現(xiàn)和凝固性壞死形態(tài)的改變主要來(lái)自于輻照中焦域處由于溫度升高所致沸騰泡對(duì)回聲的散射和對(duì)HIFU束的遮擋； 3.PCD系統(tǒng)所采信號(hào)的頻譜中四次諧波的增大可能與焦域處的沸騰泡有關(guān),若上述關(guān)系成立,則當(dāng)焦域處的溫度約為80℃時(shí),出現(xiàn)沸騰泡； 4. pHIFU輻照中焦域處的溫升受占空比的影響,高聲功率、低占空比的pHIFU輻照可以由非熱效應(yīng)在組織內(nèi)產(chǎn)生非熱損傷,且空化效應(yīng)可能是該損傷產(chǎn)生的主要機(jī)制； 5.B超可用于pHIFU輻照所致非熱損傷的監(jiān)控,但其監(jiān)控的算法、有效性、準(zhǔn)確性等需要進(jìn)一步研究。
[Abstract]:Research background
High Intensity Focused Ultrasound (HIFU), as a new noninvasive treatment, has been used in the treatment of various clinical diseases, such as uterine myoma, liver cancer, kidney cancer, bone tumor, breast cancer, allergic rhinitis, arthritis, cervicitis and other non tumor diseases, and has achieved good results. The therapeutic effect of.HIFU is based on the principle of focusing the low energy ultrasound beam in vitro to the focus of the body and forming a high energy focus. The thermal effect, the cavitation effect and the mechanical effect of ultrasound on the biological tissue increase to more than 56 degrees centigrade, leading to the formation of irreversible solidification necrosis of the tissue, but it does not affect the tissue. The normal tissue around it, so as to achieve the purpose of treatment.
As a non invasive treatment, it is necessary to have reliable and accurate monitoring methods. The monitoring methods currently used are B-ultrasound and Magnetic Resonance Imaging (MRI). The B-ultrasonic monitoring system has the advantages of good real-time, low price, and good compatibility with HIFU equipment, and the HIFU equipment monitored by B-ultrasound has been widely used in clinic. The principle of controlling the emergence of strong echoes in the immediate B-ultrasound image after HIFU irradiation is a symbol for the completion of a unit treatment. However, for the reason of the emergence of the strong echo, some scholars have pointed out that the emergence of strong echoes is mainly caused by cavitation bubbles produced by the cavitation behavior in the target area of the HIFU; and some scholars point out that the target area is the target area. The boiling bubble produced by the rise of temperature.
The solidified necrosis formed in the tissue after HIFU irradiation should be ellipsoid, but in some cases the morphology of the necrosis will change, in the form of water droplets and even triangles. The reason for the change of the morphology is also concentrated on the vacuoles and boiling bubbles that are shielded by the irradiation of the HIFU beam.
At present, the main mechanism used for HIFU therapy is the thermal mechanism, but the other mechanism, cavitation mechanism, can produce extreme physical phenomena such as high temperature, high pressure, high speed jet and so on, which can cause damage to tissue. And some researchers point out that the emergence of strong echo in HIFU irradiation means overtreatment, that is, excessive deposition of energy. The high temperature of the target area affects the safety of the treatment. Other researchers point out that the application of pulse HIFU (pulsed High Intensity Focused Ultrasound, pHIFU) can avoid the obvious temperature rise in the target area, thus using its non thermal effect.
Based on the above background, this study, based on a commercial HIFU tumor treatment system, selects different irradiation parameters and irradiate isolated bovine liver tissues to produce cavitation bubbles and / or boiling bubbles at the focal region. The ultrasound images are collected immediately after irradiation, compared with the image of the same position before irradiation, and the bovine liver tissue is dissected and the HIFU spoke is preliminarily studied. The effects of hollowing and boiling bubbles on the morphological changes of echo enhancement and coagulation necrosis at the focal region. In addition, this study also uses pHIFU to irradiate bovine liver tissue in vitro, using its non thermal effect, especially the cavitation effect to tissue damage, and the damage mechanism and B ultrasonic monitoring of its damage mechanism are preliminarily studied.
objective
1. preliminary study of the causes of strong echoes in B-mode ultrasound after HIFU irradiation.
2. the causes of morphologic changes of coagulative necrosis induced by HIFU irradiation were preliminarily studied.
3. irradiating tissues in vitro with pHIFU, and studying the feasibility of non thermal damage.
4. preliminary study on the mechanism of pHIFU radiation induced non thermal injury and the feasibility of B-mode monitoring.
Method
Effects of cavitation and boiling on the morphology of hyperechoic and coagulative necrosis of B-ultrasound in vitro irradiated by 1.HIFU
1.1 experimental materials: fresh isolated bovine liver tissues in 6 hours after slaughtering were cut into about 100mm x 100mm x 60mm size in less blood vessels and connective tissues and degassed in physiological saline for 30min.
1.2 experimental instruments and equipment: JC200 HIFU tumor treatment system (concave spherical focus, B ultrasonic monitoring, frequency 0.94MHz); passive cavitation detection (Passive Cavitation Detection, PCD) system: planar piezoelectric transducer (central frequency 0.5MHz and 5MHz), LabVIEW development platform, water immersion data line and so on; temperature acquisition system: E type thermocouple, temperature patrol A test instrument, a data acquisition program and a computer, etc.
1.3 the method of experiment:
(1) correction of HIFU sound output;
(2) the isolated bovine liver tissue after HIFU degassing was irradiated with 20mm at a depth of 20mm, and the irradiation parameters were: 50W * 10s, 50W x 80s, 100W * 10s, 150W x 5S, 200W * x and X * x;
(3) in the process of HIFU irradiation, the PCD system is used to collect the acoustic emission signals at the focal region (acoustic emissions, mainly as a cavitation signal), and then the amplitude of the second harmonic and the four harmonic is changed with the radiating time of the fast Fu Liye transform (Fast Fourier Trans form at ion, FFT). The signal is also filtered by band pass filter (3 Root Mean Square (RMS) was calculated after the band elimination filter (filtered the high order harmonics in the passband), and the RMS curve with the irradiation time was obtained; 7MHz Mean was used.
(4) the temperature of the focal region was recorded by the temperature collection system in HIFU irradiation, and the curves of the change with the irradiation time were plotted, and the 6 experiments were repeated to analyze the highest temperature at the focal region.
(5) after the irradiation of HIFU, the B-mode ultrasound images were collected and compared with the B-ultrasound images at the same location before the irradiation, and the results were repeated 20 times.
(6) after HIFU irradiation, the bovine liver tissue was cut into 1 ~ 2mm thick slices, and the maximum area of the coagulation necrosis was found. The preliminary experimental study on the non thermal damage caused by the necrotic morphologic.2. pulse HIFU irradiation in vitro tissue was observed.
2.1 experimental materials: the same;
2.2 experimental instruments and equipment: the same;
2.3 the method of experiment:
(1) correct the HIFU output and adjust the HIFU output to pulse mode.
(2) the irradiated parameters of bovine liver tissue after degassing were irradiated by pHIFU.
(3) the PCD system is used to collect the cavitation signal at the focal region and FFT transform. The temperature of the focal region is obtained by the temperature acquisition system, and the change curve with the irradiation time is drawn, and the highest temperature in the focal region at the 6 irradiation is obtained.
(4) after the irradiation, the B-mode ultrasound images were collected and compared with the b-sonograms at the same location before the irradiation, and the change of the gray level of the target area was calculated.
(5) after irradiation, the bovine liver tissue was cut into thin slices of 1 ~ 2mm. The maximum area of the injury was found and the damage morphology was observed. The specimens were stained with hematoxylin-eosin (HE) and observed under light microscope.
Acoustic power (W) duty cycle pulse repetition frequency (Hz) time of irradiation (s) depth (mm) 1%602%305004203%204%15 result
1. all the secondary harmonics in all the HIFU irradiated parameters are visible, and the RMS of broadband noise in the HIFU irradiation with the sound power of 50W and 100W does not increase; RMS begins to be smaller and then increases in the HIFU irradiation of the sound power of 150W, and the HIFU irradiation with the sound power of 200W is larger than that of the RMS, and it has a weakening trend in the irradiation of the 5S.
The 2. parameters are 50W x 10s, 50W x 80s, 100W x 10s, 150W x 5S, 200W x 2S, 200W * 5S and the focal regions of the focal region are 62.40 + 6.50 C, 93.61 + 2.46, 67.29 + 2.56, 77.84 + 6.96, 75.69 + 5.18 and 88.10 + 4.06.
The 3. parameters were 50W * 10s, 100W x 10s, 150W * 5S and 200W x 2S. There was no strong echo (the occurrence rate of strong echo was 0,15%, 10% and 5%). The morphology of coagulation necrosis was more regular. The other 2 parameters were observed in the immediate B-ultrasound image after HIFU irradiation (the occurrence rate of strong echo was 95%), and necrosis after irradiation. Morphological changes;
The four harmonics in the 4. parameters of 50W * 80s and 200W x 5S increase in the HIFU irradiation, and the RMS of the wideband noise decreases after the increase of the four harmonic waves in the HIFU irradiation of the 200W sound power; the non thermal damage is a hole like and no solid content after 5. pHIFU irradiation.
Under 6.500W sound power, the highest temperature in the focal region of pHIFU irradiated from 1% to 4% occupying space ratio is 41.19 + 1.42 C, 45.73 + 1.92, 53.07 + 2.09 and 64.13 + 2.56, and there are obvious wide-band noise in the radiation.
7. after pHIFU irradiation, the intensity of the target area decreases and the echo weakens.
conclusion
1. the effects of cavitation bubbles and boiling bubbles on focal radiation in HIFU irradiation are different.
2. HIFU after irradiation, the appearance of strong echo and the change of the morphology of coagulation necrosis mainly come from the scattering of the ebulliate to the ebulliate and the occlusion of the HIFU beam in the irradiated focal region due to the increase of temperature.
The increase of the four harmonic in the frequency spectrum of the signal produced by the 3.PCD system may be related to the boiling bubble in the focal region. If the above relationship is established, the boiling bubble appears when the temperature of the focal region is about 80 C.
In 4. pHIFU radiation, the temperature rise in the focal region is affected by the duty ratio. The pHIFU irradiation with high sound power and low duty ratio can produce non thermal damage in the tissue by the non thermal effect, and the cavitation effect may be the main mechanism of the damage.
5. B ultrasound can be used to monitor the non thermal damage caused by pHIFU radiation. However, the algorithm, validity and accuracy of its monitoring should be further studied.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R318.0

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4 姬軍;潘美玲;張春霞;;超聲圖像的質(zhì)量評(píng)價(jià)[J];醫(yī)療衛(wèi)生裝備;2010年12期

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6 張麗萍,朱曉蘭,陳松,赫雙赤,張紅,李衛(wèi);小腸平滑肌肉瘤的聲像圖表現(xiàn)[J];中國(guó)腫瘤臨床與康復(fù);1997年02期

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10 宋麗萍,趙芳,王柳松,馬維田;彩色多普勒超聲在大腸癌診斷中的應(yīng)用價(jià)值[J];實(shí)用腫瘤學(xué)雜志;2000年02期

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